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Sun-Wei Guo

Publications and source records attributed to Sun-Wei Guo.

At least 19 recordsLinked to original sources
PubMed2007

Two unsuccessful clinical trials on endometriosis and a few lessons learned.

In 1999, a phase II clinical trial on the use of fulvestrant to treat endometriosis was launched; yet after 7 years there is still no report on its outcome. In 2005, another trial on the use of raloxifene to treat endometriosis was terminated early due to unfavorable outcome. The two apparently unsuccessful clinical trials on endometriosis have taught us a few important lessons. First, we need to understand endometriosis through more basic research. We have also been reminded that human endometriosis trials differ from animal studies; anatomy and physiology are often divergent, and outcome measures are certainly different. Ectopic endometrium can differ significantly from eutopic tissue, and this issue needs to be more thoroughly explored. We believe human cell lines will prove to be an inexpensive and valuable tool for future preliminary evaluation of medical therapies as well as discerning pathophysiologic processes of the disease. Based on our current understanding of endometriosis, some concrete benchmarks can be established for testing or screening potential compounds in vitro. Finally, estrogen receptor modulators are often tissue-, cell-, and context-specific in their actions; they should not be simplistically grouped together nor should extrapolations from one compound to another be undertaken in a cavalier manner.

Adult↗
PubMed2006

Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis.

OBJECTIVE: Since endometriosis is a persistent disease with substantial gene dysregulation, there must be cellular memory of some sort that constitutes a unique cell identity for endometriotic cells. Epigenetic regulation, especially through DNA methylation, is a flexible, yet stable, mechanism for maintaining such a cellular memory. The aim of this study was to determine gene expression levels of DNMT1, DNMT3A, and DNMT3B, the three genes coding for DNA methyltransferases that are responsible for methylation. DESIGN: Cross-sectional measurements of gene expression levels of DNMT1, DNMT3A, and DNMT3B on endometriotic tissue. SETTING: Academic. PATIENT(S): Seventeen patients with laparoscopically confirmed endometriosis and 8 healthy women who underwent tubal sterilization who were free of endometriosis were recruited for the study. INTERVENTION(S): Epithelial cells were harvested from tissue samples by laser capture microdissection and messenger RNA abundance was measured by quantitative real-time reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): The expression levels of these genes in epithelial cells from 13 ectopic endometrial tissue samples, 10 eutopic endometrial tissue samples taken from women with endometriosis, and 8 normal endometrial tissue samples from women without endometriosis. RESULT(S): The genes DNMT1, DNMT3A, and DNMT3B were over-expressed in the ectopic endometrium as compared with normal control subjects or the eutopic endometrium of women with endometriosis, and their expression levels were correlated positively with each other. CONCLUSION(S): The aberrant expression of these genes suggests that aberrant methylation may be rampant in endometriosis. This also provides a strong piece of evidence that endometriosis ultimately may be an epigenetic disease.

Adult↗
PubMed2006

Sources of heterogeneities in estimating the prevalence of endometriosis in infertile and previously fertile women.

OBJECTIVE: To identify possible sources of heterogeneity in estimates of the prevalence of endometriosis in previously fertile women and in women with infertility. DESIGN: A pooled analysis of previously published studies reporting prevalence estimates. SETTING: Academic. PATIENTS: None. INTERVENTIONS: None. MAIN OUTCOME MEASURES: None. RESULTS: There were tremendous heterogeneities in prevalence estimates for both the fertile and infertile groups. In addition, the prevalence estimates increased with the year of publication, but decreased with sample size. For previously fertile women, the heterogeneity in prevalence estimates was no longer significant after the effects of sample size and year of publication on estimates were taken into account. In the infertile group, however, there was still a sizeable heterogeneity unaccounted for after both sample size and year of publication were taken into account. CONCLUSIONS: A single prevalence estimate for the entire fertile or infertile group may be too simplistic at best. More precise prevalence estimates, likely to be age-dependent, await carefully designed and executed studies that will also record covariates such as age at surgery and referral patterns.

Adolescent↗
PubMed2006

Nuclear factor-kappab (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large?

Endometriosis, defined as the ectopic presence of endometrial glandular and stromal cells outside the uterine cavity, is a common benign gynecological disorder with an enigmatic pathogenesis. Many genes and gene products have been reported to be altered in endometriosis, yet some of them may not be major culprits but merely unwitting accomplices or even innocent bystanders. Therefore, the identification and apprehension of major culprits in the pathogenesis of endometriosis are crucial to the understanding of the pathogenesis and would help to develop better therapeutics for endometriosis. Although so far NF-kappaB only has left few traces of incriminating fingerprints, several lines of investigation suggest that NF-kappaB, a pivotal pro-inflammatory transcription factor, could promote and maintain endometriosis. Various inflammatory agents, growth factors, and oxidative stress activate NF-kappaB. NF-kappaB proteins themselves and proteins regulated by them have been linked to cellular transformation, proliferation, apoptosis, angiogenesis, and invasion. Interestingly, all existing and nearly all investigational medications for endometriosis appear to act through suppression of NF-kappaB activation. In endometriotic cells, NF-kappaB appears to be constitutively activated, and suppression of NF-kappaB activity by NF-kappaB inhibitors or proteasome inhibitors suppresses proliferation in vitro. Viewing NF-kappaB as a major culprit, an autoregulatory loop model can be postulated, which is consistent with existing data and, more importantly, can explain several puzzling phenomena that are otherwise difficult to interpret based on prevailing theories. This view has immediate and important implications for novel ways to treat endometriosis. Further research is warranted to precisely delineate the roles of NF-kappaB in the pathogenesis of endometriosis and to indict and convict its aiders and abettors.

Endometriosis↗
PubMed2006

Meta-analysis of vitamin D receptor polymorphisms and type 1 diabetes: a HuGE review of genetic association studies.

Several polymorphisms in the vitamin D receptor (VDR) gene have been reported to be associated with the risk of developing type 1 diabetes, yet published findings have been conflicting. In this study, the authors attempted to evaluate the evidence regarding the association. They searched all relevant reports from original papers published from 1997 to December 2005. Predefined criteria were used to identify 1) case-control association studies examining the FokI (11 studies), BsmI (13 studies), ApaI (9 studies), and TaqI (7 studies) polymorphisms and 2) a few family-transmission studies with analysis of these four polymorphisms. In random-effects modeling, the 95% confidence intervals of the summary odds ratios for all four polymorphisms included 1, indicating no effect. Except for FokI, no heterogeneity was found. The 95% confidence intervals of the transmission proportions all included 0.5, indicating no effect. Thus, the authors found no evidence for an association between VDR gene polymorphisms and type 1 diabetes risk in either case-control studies or family-transmission studies. In fact, a reanalysis of previously published data (McDermott et al., Diabetologia 1997;40:971-5) indicated no evidence of an association as reported.

Case-Control Studies↗
PubMed2006

Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780.

BACKGROUND: All current major medications in treating endometriosis are effective in treating pain, most likely through suppression of proliferation of the implants, yet their effectiveness is relatively short term and they all have many undesirable, and sometimes severe, side effects. There is pressing need for novel, more effective medications in treating endometriosis with less and/or milder side effects. METHODS: Using a recently established immortalized endometrial stromal cell line, we carried out cell proliferation assays for cells treated with trichostatin A (TSA), RU486, CDB-2914, and N-acetylcysteine, and ICI 182780. Gene expression levels for PR-A, PR-B, AR, Fas and FasL were measured. Protein expression levels for ERalpha, ERbeta, and AR were also measured. RESULTS: Cell proliferation assay results for NAC, H2O2, CDB, and RU486 were nearly identical or similar to what have been reported based on primary cell cultures or in vivo studies. TSA, CDB, RU486 and NAC all had various antiproliferative effects. TSA had a more potent and longer lasting antiproliferative effect than CDB and NAC, even in the presence of an oxidant, H2O2. Its antiproliferative effect was concentration-dependent. ICI did not have a significant antiproliferative effect. PR-A, PR-B, AR, and FasL expression were all increased as compared with untreated cells. CONCLUSIONS: The cell line appears to be an adequate model for stromal components of endometriotic implants. That ICI has no inhibitory effect on endometrial proliferation may explain why a phase II clinical trial on its use to treat endometriosis did not advance to later stages. The upregulation of PR-B and AR may be responsible for antiproliferative effects induced by TSA, a histone deacetylase inhibitor (HDACI). HDACIs may be promising therapeutics in treating endometriosis due to their antiproliferative effects as well as the potential to restore gene dysregulation through chromatin remodeling.

Acetylcysteine↗
PubMed2006

Genomic alterations in ectopic and eutopic endometria of women with endometriosis.

BACKGROUND/AIMS: Ectopic and eutopic endometria of women with endometriosis have been shown to contain genomic alterations. In this study, we sought to identify genomic alterations in both ectopic and eutopic endometria of 5 women with endometriosis and to examine whether the two tissues share any genomic alterations. We also attempted to classify tissue samples based on the alteration profiles. METHODS: Laser capture microdissection was used to harvest epithelial cells. High-resolution comparative genomic hybridization microarrays were used to identify genomic alterations in eutopic and ectopic endometria from 5 women with endometriosis. The results were validated by real-time RT-PCR and loss of heterozygosity analysis. RESULTS: All 5 patients had genomic alterations in their eutopic and ectopic endometria. The ectopic and eutopic endometria shared a sizable portion of genomic alterations. Cluster analysis of the genomic alteration profile correctly and consistently classified tissue samples from the 5 patients into two groups: peritoneal implants and ovarian cysts. CONCLUSIONS: The correct classification of tissue samples into two groups suggests that these two subtypes of endometriosis may have distinct genomic alteration profiles and are thus distinct entities, as previously proposed. The shared alterations are likely the ones that harbor genes responsible for an increased propensity of endometrial debris to implant to the ectopic sites and for early events that lead to the establishment of lesions. Alternatively, these shared alterations may harbor genes that are dysregulated in both eutopic and ectopic endometria. The identified genomic alterations should help to zero in genes involved in the pathogenesis of endometriosis in future studies.

Adult↗
PubMed2006

The prevalence of endometriosis in women with chronic pelvic pain.

BACKGROUND: The 2004 American College of Obstetrics and Gynecology clinical management guideline states that the prevalence of endometriosis is approximately 33% in women with chronic pelvic pain (CPP). This estimate came from a review showing that 28% of adult women with CPP were found to have endometriosis. The prevalence of 28% in adult women was arrived based on a compilation of 11 published studies. Yet even within the 11 studies, the reported prevalence of endometriosis varies wildly, ranging from 2 to 74%. Such an astounding variation or heterogeneity raises the question whether it is appropriate to use a single prevalence of endometriosis for all women with CPP. METHODS: We sought to identify possible sources of heterogeneities in the estimation of prevalence of endometriosis in women with CPP. We included more studies that reported prevalence estimates than the review, and examined the effect of sample size and the year of publication on the heterogeneity. RESULTS: The year of publication is positively associated with the prevalence estimate, which may indicate an increasing awareness of various appearances of endometriosis, or the prevalence of endometriosis may have increased among women with CPP. An alternative analysis with removal of four studies reporting highest prevalence estimates indicated that sample size is negatively associated with the prevalence estimates while the year of publication became only marginally significant. CONCLUSIONS: There are identifiable sources of heterogeneity in prevalence estimates, with the year of publication, sample size, and difference in evaluation of CPP being three apparent sources. Having a single prevalence estimate for all women with CPP may be too simplistic at best. The true prevalence is very likely to be higher than 33%.

Adult↗
PubMed2005

Glutathione S-transferases M1/T1 gene polymorphisms and endometriosis: a meta-analysis of genetic association studies.

In view of the controversies surrounding the glutathione S-transferases (GST) M1/T1-endometriosis association, a meta-analysis of the GSTM1/GSTT1 genetic association studies of endometriosis was performed. In this meta-analysis involving 14 GSTM1 studies with 1539 cases and 1805 controls and nine GSTT1 studies with 746 cases and 834 controls, respectively, substantial heterogeneities among studies were found. In addition, asymmetry in funnel plot was evident, which is likely to stem from publication bias, given no apparent indication of true heterogeneity. The bias appears to be prominent for GSTM1 studies, but is less so for GSTT1 studies. After correction for this bias, there is no evidence that women with GSTM1 null genotype have increased risk of developing endometriosis as compared with women with other genotypes. For GSTT1, the risk associated with the null genotype is 29% higher than other genotypes. However, even this estimate should be viewed with a large grain of salt, because the estimate could easily lose its statistical significance if there is a realistic 69-80% publication probability.

Adult↗
PubMed2005

The association of endometriosis risk and genetic polymorphisms involving dioxin detoxification enzymes: a systematic review.

Genetic polymorphisms involving genes encoding for dioxin detoxification enzymes have been implicated as a risk factor for endometriosis, but individual studies have been equivocal and controversial. We therefore performed a systematic review of 10 studies on association of endometriosis and various genes involved in dioxin detoxification process excluding GSTM1/GSTT1. We found that almost all genetic variants involving CYP1A1, CYP2E1, EPHX1, AHR, ARNT, AHRR, and NAT1 that have been investigated by single studies show no association with endometriosis. Two genetic variants were reported to be associated with endometriosis, with each variant only investigated by a single study and there has been no independent confirmation so far. For CYP1A1 MspI polymorphisms, women with +/- and +/+ genotype have about 40% of increased risk of endometriosis as compared with women of -/- genotype. However, there is no strong indication that CYP1A1 MspI polymorphism is consistently associated with endometriosis. For NAT2 polymorphisms, there is no evidence that it is associated with endometriosis.

Aryl Hydrocarbon Receptor Nuclear Translocator↗
PubMed2005

Association of endometriosis risk and genetic polymorphisms involving sex steroid biosynthesis and their receptors: a meta-analysis.

Endometriosis is a sex steroids-dependent disease. It has been postulated that certain genetic polymorphisms involved in sex steroids biosynthesis and metabolisms may be associated with increased risk of developing endometriosis. Despite a deluge of reports of positive associations of endometriosis with numerous polymorphisms involving sex steroids production and metabolism, the results are often conflicting. We performed a meta-analysis of 12 association studies on 5 genes (CYP17, CYP19, AR, PR and ER). We found that many reported positive findings were not supported by the data due to faulty analysis. There have been no functional data that support a putative relationship of these genetic polymorphisms with endometriosis. A handful of positive findings so far have not been independently replicated, and should be viewed as preliminary. In addition, these findings should be counterbalanced by legitimate concerns of multiple comparisons, small prior probability of association with a particular polymorphism, proper selection of controls, and lack of replication (at least until now). In future association studies, it may be productive to put more thought to study design, execution, and data analysis.

Aromatase↗
PubMed2005

Transcriptional characterizations of differences between eutopic and ectopic endometrium.

Endometriosis, defined as the presence of endometrial glandular and stromal cells outside the uterine cavity, is a common gynecological disease with poorly understood pathogenesis. Using laser capture microdissection and a cDNA microarray with 9600 genes/expressed sequence tags (ESTs), we have conducted a comprehensive profiling of gene expression differences between the ectopic and eutopic endometrium taken from 12 women with endometriosis adjusted for menstrual phase and the location of the lesions. With dye-swapping and replicated arrays, we found 904 genes/ESTs that are differentially expressed. We validated the gene expression using real-time RT-PCR. We found that the expression patterns of these genes/ESTs correctly classified the 12 patients into ovarian and nonovarian endometriosis. We identified gene clusters that are location-specific. In addition, we identified several biological themes using Expression Analysis Systematic Explorer. Finally, we identified 79 pathways with over 100 genes with known functions, which include oxidative stress, focal adhesion, Wnt signaling, and MAPK signaling. The identification of these genes and their associated pathways provides new insight. Our findings will stimulate future investigations on molecular genetic mechanisms underlying the pathogenesis of endometriosis.

Base Sequence↗
PubMed2005

Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis.

OBJECTIVE: HOXA10, expressed in endometrium, plays an important role in uterine receptivity at the time of implantation. In the endometrium of women with endometriosis, its expression is reduced. The aim of this study was to determine whether the observed aberrant expression of HOXA10 is caused by aberrant methylation of the gene. STUDY DESIGN: Endometrial tissues were collected from 6 women with laparoscopically confirmed endometriosis, and 4 women who underwent tubal ligation and were confirmed to have no endometriosis. In addition, menstrual blood from 5 women with no gynecologic complaints was collected and also used as controls. Methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing were performed in 3 fragments in 2 regions of HOXA10 to detect difference in methylation patterns. Real-time reverse transcriptase (RT)-PCR was also performed to measure expression levels of HOXA10 in select cases and controls. RESULTS: In all 3 fragments, there were highly statistically significant differences in methylation patterns between women with endometriosis and those without endometriosis. The expression level of HOXA10 was lower in women with endometriosis than those without, as previously reported. CONCLUSION: There is aberrant methylation in the endometrium of women with endometriosis compared with those without endometriosis. The aberrant methylation at HOXA10 may be responsible for the aberrant gene expression in the endometrium of women with endometriosis. This finding suggests that endometriosis may also be an epigenetic disease.

Base Sequence↗
PubMed2004

Genomic alterations in the endometrium may be a proximate cause for endometriosis.

OBJECTIVE: To test the hypothesis that endometriosis may originate from genomic alterations in the endometrium by genomic analysis of endometrial tissues in patients with endometriosis and compare them with those from normal controls. METHODS: Endometrial tissue samples were taken from five women with endometriosis. For controls, we used endometrial tissue samples from four women who underwent elective abortions and one sample from placenta. Using array-based comparative genomic hybridization (CGH), we determined the normal range of variation in CGH signals using normal controls. CGH results were further confirmed by real-time quantitative PCR and loss of heterozygosity analysis. RESULTS: We identified several regions of genomic alterations in all five patients. Some of these regions were the same regions identified previously in endometriotic lesions. For select markers, the genomic alterations were confirmed by real-time PCR and LOH analyses. CONCLUSIONS: There is evidence that the endometrium in women with endometriosis has genomic alterations. This is consistent with numerous reports that the endometrium of women with endometriosis differ from those of women without. Our finding suggests that genomic alterations in the endometrium may be a proximate cause for endometriosis.

Adult↗
PubMed2004

The link between exposure to dioxin and endometriosis: a critical reappraisal of primate data.

Endometriosis is a common and enigmatic disease affecting women of reproductive age. In 1993, Dr. Sherry Rier and her colleagues reported a serendipitous finding that quickly sent a shock wave through the endometriosis research community. They found that rhesus monkeys exposed daily for 4 years to dioxin developed endometriosis, with incidence and severity related to dose. The study prompted more animal and epidemiologic studies regarding the link between dioxin exposure and endometriosis. Yet, 10 years after the first piece of evidence was reported, the primate data are still equivocal, and the human data supporting the dioxin-endometriosis association are scanty and conflicting. While many reviewers of the subject recognize the need for more data, other reviewers tend to discount negative studies when reviewing positive studies. In this paper, a critical reappraisal of all evidence from human and primate data is presented. While there is evidence suggesting that exposure to dioxin may facilitate the short-term survival of endometrial implants in non-human primates, this evidence is not supported by both human and non-human primate studies evaluating the relationship between dioxin exposure and the development of spontaneous endometriosis. Weighing all converging evidence, it seems that there are no solid, credible data available at this moment to support the hypothesis that dioxin exposure may lead to the development of endometriosis.

Animals↗
PubMed2004

Statistical methods for detecting genomic alterations through array-based comparative genomic hybridization (CGH).

Array-based comparative genomic hybridization (ABCGH) is an emerging high-resolution and high-throughput molecular genetic technique that allows genome-wide screening for chromosome alterations associated with tumorigenesis. Like the cDNA microarrays, ABCGH uses two differentially labeled test and reference DNAs which are cohybridized to cloned genomic fragments immobilized on glass slides. The hybridized DNAs are then detected in two different fluorochromes, and the significant deviation from unity in the ratios of the digitized intensity values is indicative of copy-number differences between the test and reference genomes. Proper statistical analyses need to account for many sources of variation besides genuine differences between the two genomes. In particular, spatial correlations, the variable nature of the ratio variance and non-Normal distribution call for careful statistical modeling. We propose two new statistics, the standard t-statistic and its modification with variances smoothed along the genome, and two tests for each statistic, the standard t-test and a test based on the hybrid adaptive spline (HAS). Simulations indicate that the smoothed t-statistic always improves the performance over the standard t-statistic. The t-tests are more powerful in detecting isolated alterations while those based on HAS are more powerful in detecting a cluster of alterations. We apply the proposed methods to the identification of genomic alterations in endometrium in women with endometriosis.

Chromosome Aberrations↗
PubMed2003

Three color cDNA microarrays: quantitative assessment through the use of fluorescein-labeled probes.

Gene expression studies using microarrays have great potential to generate new insights into human disease pathogenesis, but data quality remains a major obstacle. In particular, there does not exist a method to determine prior to hybridization whether an array will yield high quality data, given good study design and target preparation. We have solved this problem through development of a three-color cDNA microarray platform where printed probes are fluorescein labeled, but are spectrally compatible with Cy3 and Cy5 dye-labeled targets when using confocal laser scanners possessing narrow bandwidths. This approach enables prehybridization evaluation of array/spot morphology, DNA deposition and retention and background levels. By using these measurements and the intra-slide coefficient of variation for fluorescence intensity we show that slides in the same batch are not equivalent and measurable prehybridization parameters can be predictive of hybridization performance as determined by replicate consistency. When hybridizing target derived from two cell lines to high and low quality replicate pairs (n = 50 pairs), a direct and significant relationship between prehybridization signal-to-background noise and post-hybridization reproducibility (R2 = 0.80, P < 0.001) was observed. We therefore conclude that slide selection based upon prehybridization quality scores will greatly benefit the ability to generate reliable gene expression data.

Carbocyanines↗